The overall objective of this proposal is to characterize the role of the autonomic nervous system in the production of ventricular arrhythmias during myocardial ischemia and to elucidate the mechanisms by which this system modifies the electrophysiological properties of the heart. In open-chest, whole dog studies we will manipulate (by electrical stimulation of nerves and by infusion of drugs) both the adrenergic and cholinergic limbs of the autonomic nervous system, individually and simultaneously, to determine whether specific combinations of autonomic stimulation are more arrhythmogenic or antiarrhythmic than others and how the autonomic effects relate to the site of induced myocardial ischemia. Parallel experiments will be performed on isolated Purkinje fibers and ventricular muscle to further characterize the electrophysiological effects of adrenergic-cholinergic interaction. During both the in vivo and in vitro studies, experiments will also be performed to elucidate the mechanism of the autonomic modification of the electrophysiological properties of the myocardium by investigating the myocardial metabolism of cyclic AMP and cyclic GMP. During these studies we will directly measure tissue levels of these cyclic nucleotides and pharmacologically manipulate their levels while also determining the electrophysiological properties of the tissue. It is hoped that these basic studies will suggest therapeutic interventions designed to prevent the development of ventricular fibrillation, the most likely cause of sudden death in patients with coronary artery disease.